Arylpiperazines having activity at the serotonin 1A receptor

ABSTRACT

Described herein is a compound of the formula                    
     wherein 
     Ar′ is a mono or bicyclic aromatic or heteroaromatic radical substituted with one to three substituents selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylhalo, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl or halo; 
     R 1  is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio; 
     R 2  is phenyl, naphthyl or (C 3 -C 12 )cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylhalo, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl or halo; 
     R 3  is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylhalo, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl or halo; 
     X is —(C═O)—; 
     or a pharmaceutically acceptable salt racemate, optical isomer or solvate thereof.

CROSS REFERENCE

This application is a Divisional Application of U.S. Ser. No.10/022,043, filed Dec. 18, 2001, which is a Divisional Application ofU.S. Ser. No. 09/753,645, filed Jan. 3, 2001, which issued Mar. 19,2002, as U.S. Pat. No. 6,358,958, which is a Divisional Application ofU.S. Ser. No. 09/208,553, filed Dec. 9, 1998, which issued May 29, 2001as U.S. Pat. No. 6,239,135, which claims priority to U.S. ProvisionalApplication No. 60/089,589, filed Jun. 17, 1998, and U.S. ProvisionalApplication Nos. 60/069,722 and 60/069,791, both filed Dec. 16, 1997,the contents of which are herein incorporated by reference.

FIELD OF THE INVENTION

The present invention belongs to the fields of pharmacology andmedicinal chemistry, and provides new pharmaceuticals which are usefulfor the treatment of diseases which are caused or affected by disordersof the serotonin-affected neurological systems, particularly thoserelating to the 1_(A) receptor.

BACKGROUND OF THE INVENTION

Pharmaceutical researchers have discovered in recent years that theneurons of the brain which contain monoamines are of extreme importancein a great many physiological processes which very strongly affect manypsychological and personality-affecting processes as well. Inparticular, serotonin (5-hydroxytryptamine; 5-HT) has been found to be akey to a very large number of processes which affect both physiologicaland psychological functions. Drugs which influence the function ofserotonin in the brain are accordingly of great importance and are nowused for a surprisingly large number of different therapies.

The early generations of serotonin-affecting drugs tended to have avariety of different physiological functions, considered from both themechanistic and therapeutic points of view. More recently, it has becomepossible to study the function of drugs at individual receptors in vitroor ex vivo, and it has also been realized that therapeutic agents with asingle mechanism of action are often advantageous to the patient.Accordingly, the objective of research now is to discover not onlyagents which affect only functions of serotonin, but agents which affectonly a single function of serotonin, at a single identifiable receptor.

The present invention provides compounds which have highly selectiveactivity as antagonists of the serotonin 1_(A) receptor.

SUMMARY OF THE INVENTION

The present invention provides a series of new aryl piperazinecompounds, methods of using them for pharmaceutical purposes, andpharmaceutical compositions whereby the compounds may be convenientlyadministered.

The invention also provides methods of antagonizing, the 5HT-1_(A)receptor, and therapeutic methods which are related to their effect onthe 5HT-1_(A) receptor. Such methods of treatment include, particularly,methods of alleviating the symptoms caused by withdrawal or partialwithdrawal from the use of tobacco or of nicotine, comprising theadministration to a patient in need of such treatment of a compound ofFormula I

wherein

Ar′ is a mono- or bi-cyclic aryl or heteroaryl radical substituted withone to three substituents selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylhalo, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenylor halo;

R¹ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio;

R² is phenyl, naphthyl or (C₃-C₁₂)cycloalkyl substituted with one or twosubstituents selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylhalo, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenylor halo;

R³ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylhalo, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl or halo;

X is —C(═O)—, —CHOH— or —CH₂—;

or a pharmaceutically acceptable salt, racemate, optical isomer orsolvate thereof.

Further, such therapeutic methods include methods of treatment ofanxiety, depression, hypertension, cognitive disorders, psychosis, sleepdisorders, gastric motility disorders, sexual dysfunction, brain trauma,memory loss, eating disorders and obesity, substance abuse,obsessive-compulsive disease, panic disorder and migraine.

A further treatment method provided by the present invention is a methodfor potentiating the action of a serotonin reuptake inhibitor,comprising administering to a patient an effective amount of a compoundof Formula I in combination with the serotonin reuptake inhibitor.

More specifically, the present invention provides compounds of formulaIa;

or the pharmaceutically acceptable salts thereof.

The compounds of formula Ia are enclosed within the scope of thecompounds of Formula I and are therefore useful for the methodsdescribed herein for Formula I. For example, the present inventionprovides methods of antagonizing, the 5HT-1_(A) receptor, andtherapeutic methods which are related to their effect on the 5HT-1_(A)receptor. Such methods of treatment include, particularly, methods ofalleviating the symptoms caused by withdrawal or partial withdrawal fromthe use of tobacco or of nicotine, comprising the administration to apatient in need of such treatment, an effective amount of a compound offormula Ia. Further, such therapeutic methods include methods oftreatment of anxiety, depression, hypertension, cognitive disorders,psychosis, sleep disorders, gastric motility disorders, sexualdysfunction, brain trauma, memory loss, eating disorders and obesity,substance abuse, obsessive-compulsive disease, panic disorder andmigraine.

In addition, the present invention provides a method for potentiatingthe action of a serotonin reuptake inhibitor, comprising administeringto a patient an effective amount of a compound of formula Ia incombination with the serotonin reuptake inhibitor.

The invention further provides a method of assisting a patient inceasing or reducing their use of tobacco or nicotine comprisingadministering to a patient an effective amount of a compound of theFormula I or formula Ia.

This invention also encompasses novel processes for the synthesis of thecompounds of formula I and formula Ia, the synthesis of novelintermediates thereof, and further encompasses novel intermediates perse.

DESCRIPTION OF PREFERRED EMBODIMENTS

In the present document, all descriptions of concentrations, amounts,ratios and the like will be expressed in weight units unless otherwisestated. All temperatures are in degrees Celsius.

The Compounds

It is believed that the general description of the compounds above issufficient to explain their nature to the skilled reader; attention tothe Examples which follow is also encouraged. Some additionaldescription will be provided to assure that no misunderstanding occurs.

In the general description, the general chemical terms are all used intheir normal and customary meanings. For example, the small alkyl andalkoxy groups, such as (C₁-C₆)alkyl and (C₁-C₆)alkoxy groups include,depending on the size of the groups, methyl, ethyl, propyl, isopropyl,n-butyl, s-butyl, pentyl, 3-methylbutyl, hexyl, and branched hexylgroups, and the corresponding alkoxy groups, as may be allowed by theindividually named groups. Where a number of possible substituent groupsare permitted on a group, such as the one to three alkyl, alkoxy or halogroups permitted on an Ar group, it will be understood by the readerthat only substitution which is electronically and sterically feasibleis intended.

The term “alkenyl” as used herein represents an unsaturated branched orlinear group having at least one double bond. Examples of such groupsinclude radicals such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl aswell as dienes and trienes of straight and branched chains.

The term “alkynyl” denotes such radicals as ethynyl, propynyl, butynyl,pentynyl, hexynyl as well as di- and tri-ynes.

The term “(C₁-C₆)alkylthio” defines a straight or branched alkyl chainhaving one to six carbon atoms attached to the remainder of the moleculeby a sulfur atom. Typical (C₁-C₆)alkylthio groups include methylthio,ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like.

The term “(C₁-C₆)alkylhalo” refers to alkyl substituents having one ormore independently selected halo atoms attached at one or more availablecarbon atoms. These terms include chloromethyl, bromoethyl,trifluoroethyl, trifluoromethyl, 3-bromopropyl, 2-bromopropyl,3-chlorobutyl, 2,3-dichlorobutyl, 3-chloro-2-bromo-butyl,trichloromethyl, dichloroethyl, 1,4-dichlorobutyl, 3-bromopentyl,1,3-dichlorobutyl, 1,1-dichloropropyl, and the like. More preferred(C₁-C₆)alkylhalo groups are trichloromethyl, trichloroethyl, andtrifluoromethyl. The most preferred (C₁-C₆)alkylhalo is trifluoromethyl.

The term “(C₃-C₈)cycloalkyl” includes groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Theterm “(C₃-C₈)cycloalkyl” includes (C₃-C₆)cycloalkyl.

The term “(C₃-C₈)cycloalkenyl” represents an olefinically unsaturatedring having 3 to 8 carbon atoms including groups such as cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,and the like. The term “(C₃-C₈)cycloalkenyl” includes(C₃-C₆)cycloalkenyl.

The term “aryl” represents phenyl or naphthyl.

The term “bicyclic” represents either an unsaturated or saturated stable7- to 12-membered bridged or fused bicyclic carbon ring. The bicyclicring may be attached at any carbon atom which affords a stablestructure. The term includes, but is not limited to, naphthyl,dicyclohexyl, dicyclohexenyl, and the like.

The term, “mono or bicyclic heteroaryl radical”, refers to radicalsderived from monocyclic or polycyclic, aromatic nuclei having 5 to 14ring atoms and containing from 1 to 3 hetero atoms selected from thegroup consisting of nitrogen, oxygen or sulfur. Typical heterocyclicradicals are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl,indolizinyl, isoquinolyl, benzothienyl, isoindolizinyl, oxazolyl,indolyl, carbazolyl, norharmanyl, azaindolyl, dibenzofuranyl,thianaphthenyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl,anthranilyl, purinyl, pyridinyl, phenylpyridinyl, pyrimidinyl,pyrazinyl, quinolinyl.

The terms “halo” or “halide” are used in the above formula to refer tofluoro, chloro, bromo or iodo.

The term “aprotic solvent” refers to polar solvents of moderately highdielectric constant which do not contain an acidic hydrogen. Examples ofcommon aprotic solvents are dimethylsulfoxide (DMSO), dimethylformamide,sulfolane, tetrahydrofuran, diethyl ether, methyl-t-butyl ether, or1,2-dimethoxyethane.

The term “protic solvent” refers to a solvent containing hydrogen thatis attached to oxygen, and hence is appreciably acidic. Common proticsolvents include such solvents as water, methanol, ethanol, 2-propanol,and 1-butanol.

The term “inert atmosphere” refers to reaction conditions in which themixture is covered with a layer of inert gas such as nitrogen or argon.

As used herein, the term “Me” refers to a —CH₃ group, the term “Et”refers to a —CH₂CH₃ group and the term “Pr” refers to a —CH₂CH₂CH₃group.

As used herein, the term “stereoisomer” refers to a compound made up ofthe same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. As used herein, the term“optical isomer” is equivalent to the term “enantiomer”. The terms“racemate”, “racemic mixture” or “racemic modification” refer to amixture of equal parts of enantiomers. The term “chiral center” refersto a carbon atom to which four different groups are attached.

The term “enantiomeric enrichment” as used herein refers to the increasein the amount of one enantiomer as compared to the other. A convenientmethod of expressing the enantiomeric enrichment achieved is the conceptof enantiomeric excess, or “ee”, which is found using the followingequation: ${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$

wherein E¹ is the amount of the first enantiomer and E² is the amount ofthe second enantiomer. Thus, if the initial ratio of the two enantiomersis 50:50, such as is present in a racemic mixture, and an enantiomericenrichment sufficient to produce a final ratio of 50:30 is achieved, theee with respect to the first enantiomer is 25%. However, if the finalratio is 90:10, the ee with respect to the first enantiomer is 80%. Anee of greater than 90% is preferred, an ee of greater than 95% is mostpreferred and an ee of greater than 99% is most especially preferred.Enantiomeric enrichment is readily determined by one of ordinary skillin the art using standard techniques and procedures, such as gas or highperformance liquid chromatography with a chiral column. Choice of theappropriate chiral column, eluent and conditions necessary to effectseparation of the enantiomeric pair is well within the knowledge of oneof ordinary skill in the art. In addition, the enantiomers of compoundsof formulas I or Ia can be resolved by one of ordinary skill in the artusing standard techniques well known in the art, such as those describedby J. Jacques, et al., “Enantiomers, Racemates, and Resolutions”, JohnWiley and Sons, Inc., 1981. Examples of resolutions includerecrystallization techniques or chiral chromatography.

The compounds of Formula I and formula Ia, as a class are highly active,important and particularly useful in the treatment methods of thepresent invention, but certain classes of the compounds are preferred.The following paragraphs describe such preferred classes. It will beunderstood that the preferred classes are applicable both to thetreatment methods and to the new compounds of the present invention.

The reader will understand that the preferred classes of compounds maybe combined to form additional, broader or narrower classes of preferredcompounds.

a) Ar′ is phenyl or pyridyl;

b) Ar′ is naphthyl;

c) Ar′ is pyrazinyl, pyrimidinyl, pyrrolyl, furyl, thienyl, indolyl,purinyl, imidazolyl, pyrazolyl, indolizinyl, benzofuranyl, isoquinolyl,quinolyl, benzothienyl or isoindolizinyl;

d) Ar′ is optionally substituted with (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo,(C₂-C₆)alkenyl or (C₂-C₆)alkynyl;

e) Ar′ is optionally substituted with (C₁-C₄)alkyl, (C₁-C₄)alkoxy orhalo;

f) R¹ is hydrogen;

g) R¹ is (C₁-C₆)alkyl or (C₁-C₆)alkoxy;

h) R¹ is (C₁-C₂)alkyl or (C₁-C₂)alkoxy;

i) R² is phenyl;

j) R² is (C₃-C₈)cycloalkyl;

k) R² is (C₃-C₆)cycloalkyl;

l) R² is cyclohexyl;

m) R³ is (C₁-C₆)alkyl, (C₁-C₆)alkoxy or halo;

n) R³ is (C₁-C₄)alkyl, (C₁-C₄)alkoxy or halo;

o) X is —C═O;

p) X is —CHOH; and

q) X is —CH₂.

r) formula Ia

s) the enantiomer of formula Ia wherein the [α]^(D) ₂₀ in methanol is(+).

Since the compounds of this invention are basic in nature, theyaccordingly react with any of a number of inorganic and organic acids toform pharmaceutically acceptable acid addition salts. Included withinthe scope of the invention are the mono- and di-salts. Acids commonlyemployed to form such salts are inorganic acids such as hydrochloricacid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid,and the like, and organic acids, such as p-toluenesulfonic acid,methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonicacid, succinic acid, citric acid, benzoic acid, acetic acid and thelike. Examples of such pharmaceutically acceptable salts thus are thesulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, caproate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate,phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,β-hydroxybutyrate, glycollate, tartrate, methanesulfonate,propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,mandelate and the like. Preferred pharmaceutically acceptable salts arethe monohydrochloride, dihydrochloride, monohydrobromide,dihydrobromide, Formula I/succinate(1:1), formula Ia/succinate(1:1),Formula I/succinate 2:1, formula Ia/succinate 2:1, phosphate,d-tartrate, l-tartrate or maleate. It is understood by one of ordinaryskill that hydrates of the free base or of the pharmaceuticallyacceptable salts are included within the scope of the present invention.

Many of the compounds of Formula I, including formula Ia, are opticalisomers. For example, the compounds have an asymmetric center (or chiralcenter) at the carbon atom to which R¹ and X are attached. However, whena compound of the present invention is named without an indication ofasymmetric form, any and all of the possible asymmetric forms areintended. This invention is not limited to any particular isomer butincludes all possible individual isomers and racemates.

The intermediates and final products may be isolated and purified byconventional techniques, such as, purification with chromatography usingsilica gel or recrystallization of crystalline isolates.

It will be readily appreciated by the skilled artisan that the startingmaterials which are not described are either commercially available orcan be readily prepared by known techniques from commercially availablestarting materials. All other reactants used to prepare the compounds inthe instant invention are commercially available.

The compounds of the invention are generally prepared according to thefollowing schemes.

Starting material (1) is treated with a base, preferably potassiumtert-butoxide, followed by alkylation with 2-bromomethyl-1,3-dioxolane.Other appropriate bases include sodium hydride, sodium hydroxide,potassium hydroxide, potassium carbonate, cesium carbonate and the like.

The reaction is preferably conducted in a solvent such as dimethylsulfoxide at a temperature of 15° C. to reflux, with a temperature of45-55° C. being most preferred, and is substantially complete in 1 to 24hours to prepare intermediate (2).

Treatment of (2) with an acid, such as hydrochloric acid orp-toluene-sulfonic acid in a suitable organic solvent, achieves aldehyde(3). Generally, the reaction is conducted in a protic solvent, such amixture of aqueous acid and acetone, at temperatures of from about 5° to75° C., preferably at ambient temperature.

Aldehyde (3) is coupled with the desired aryl piperidine (4) byreductive amination to prepare (5). The reaction is preferably conductedat ambient temperature in a non-reactive solvent such as dichloroethaneor methylene chloride in the presence of sodium triacetoxyborohydrideand is substantially complete in one to 24 hours. See for example A. F.Abdel-Magid, et al., J. Org. Chem., 61, 3849 (1996).

Reduction of (5) is readily accomplished using a reducing agent such assodium borohydride or, preferably, diisobutylaluminum hydride to preparethe hydroxy compound (6). The reaction is preferably conducted in anorganic solvent such as methylene chloride at temperatures of from about−20° C. to 0° C.

Further reduction of (6) to achieve product (7) may be achieved bytreatment with a reducing agent such as triethylsilane or borontrifluoride (when R² is phenyl or substituted phenyl) or by treatmentwith an acid, such as hydrochloric acid or trifluoroacetic acid, in anaprotic solvent such as tetrahydrofuran, at ambient temperature to formthe double bond, followed by hydrogenation with, for example, hydrogenand palladium on carbon.

Starting material (1) is either commercially available or can beprepared by coupling (8) [See Nahm and Weinreb, Tetrahedron Lett., 22,3815, (1981)] and (9) as described in Scheme II, below.

M is a metallic salt, such as lithium or magnesium halide. The reactionis preferably conducted under an inert atmosphere preferably nitrogen,in an aprotic solvent, such as tetrahydrofuran, at ambient temperatures.

More specifically, the compounds of formula Ia can be prepared followingthe procedure described in Scheme III. All substituents, unlessotherwise indicated, are previously defined. The reagents and startingmaterials are readily available to one of ordinary skill in the art.

In Scheme III, step A, the ester of structure (10) is treated withbenzylmagnesium chloride or benzylmagnesium bromide under standardconditions well known in the art to provide the ketone of structure(11). For example, about 1.05 to about 1.1 equivalents of a suitableamine, such as dimethylamine is dissolved in a suitable organic solvent,such as tetrahydrofuran (cooled to about −5° C.) under an inertatmosphere. The solution is warmed to room temperature and 1.0equivalents of the ester (10) are added with stirring. Thenapproximately 1.0 to 1.05 equivalents of benzylmagnesium chloride isslowly added to the solution, maintaining the temperature at about15-20° C. with a cooling bath during the addition. After addition iscomplete, the reaction is stirred at room temperature for about 1 to 2hours, then cooled to less than 0° C. and then carefully quenched with asuitable acid, such as HCl. The quenched reaction is then extracted witha suitable organic solvent, such as tert-butyl methyl ether (hereinafterreferred to as MTBE), the organic layers are-combined, dried overanhydrous magnesium sulfate, filtered and concentrated to provide ketone(11). Ketone (11) can be purified by techniques well known in the art,such as flash chromatography on silica gel with a suitable eluent, suchas ethyl acetate/hexane to provide the purified material. Alternatively,the crude ketone (11) can be carried on to step B.

In Scheme III, step B, ketone (11) is alkylated with bromoacetaldehydediethyl acetal, and then iodomethane, under conditions well known in theart to provide compound of structure (12). For example, ketone (11) isdissolved in a suitable organic solvent, such as methyl sulfoxide andtreated with about 1.05 to about 1.1 equivalents of a suitable base,such as potassium tert-butoxide. The reaction is stirred for about 15 to30 minutes and about 1.0 to about 1.05 equivalents of bromoacetaldehydediethyl acetal is added dropwise to the reaction. One of ordinary skillin the art would readily appreciate that bromoacetaldehyde dimethylacetal, bromoacetaldehyde ethylene acetal and the like may be used inplace of the corresponding diethyl acetal. The reaction mixture is thenheated to about 50° C. for about 2 to 2.5 hours. The reaction mixture isthen cooled with an ice/water bath and about 2.2 equivalents of asuitable base, such as potassium tert-butoxide is added. The reaction isallowed to stir for about 15 to 30 minutes with continued cooling andthen about 1.5 to about 1.8 equivalents of iodomethane is added dropwiseto the reaction mixture keeping the temperature of the mixture below 41°C, preferably below 21° C. After addition is complete, the reaction iswarmed to room temperature and stirred for about 1 to 4 hours. Thereaction mixture is then partitioned between water and a suitableorganic solvent, such as MTBE. The layers are separated and the organicphase is washed with water, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated under vacuum to provide the compound(12).

In Scheme III, step C, compound (12) is hydrolyzed under acidicconditions to provide aldehyde (13) in a manner analogous to theprocedure described in Scheme I. More specifically, for example,compound (12) is dissolved in a suitable organic solvent, such asacetone and treated with a suitable acid, such as hydrochloric acid. Thereaction mixture is stirred for about 1 to 3 hours at room temperature.The reaction mixture is then extracted with a suitable organic solvent,such as ethyl acetate or methylene chloride, the organic extracts arecombined, washed with brine, dried over anhydrous magnesium sulfate,filtered and concentrated under vacuum to provide aldehyde (13).Aldehyde (13) can be purified by techniques well known in the art, suchas flash chromatography on silica gel with a suitable eluent, such asethyl acetate/hexane. Alternatively, crude aldehyde (13) can be useddirectly in step D.

In Scheme III, step D, aldehyde (13) is reductively aminated, underconditions well known in the art, with piperazine (14) to provide thecompound of formula Ia in a manner analogous to the procedure describedin Scheme I. More specifically, for example, aldehyde (13) is dissolvedin a suitable organic solvent, such as methylene chloride. To thissolution is added about 1.1 equivalents of piperazine (14). Acetic acidmay optionally be added to aid in dissolution of the piperazine (14).Then about 1.2 to 1.3 equivalents of sodium triacetoxyborohydride isadded and the reaction is stirred at room temperature for about 3 to 5hours. The reaction is then quenched by addition of a suitable base,such as aqueous sodium hydroxide to provide a pH of about 10 to about12. The quenched reaction is then extracted with a suitable organicsolvent, such as methylene chloride. The organic extracts are combined,washed with brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum to provide the compound of formula Ia. Thismaterial can then be purified by techniques well known in the art, suchas flash chromatography on silica gel with a suitable eluent, such asethyl acetate/hexane.

The free base of formula Ia can be converted to the correspondingpharmaceutically acceptable salts under standard conditions well knownin the art. For example, the free base of formula Ia is dissolved in asuitable organic solvent, such as methanol, treated with one equivalentof maleic or oxalic acid for example, or two equivalents of hydrochloricacid for example, and then concentrated under vacuum to provide thecorresponding pharmaceutically acceptable salt. The residue can then bepurified by recrystallization from a suitable organic solvent or organicsolvent mixture, such as methanol/diethyl ether.

In Scheme III, step E, the (+) enantiomer of formula Ia can be separatedfrom the (−) enantiomer using techniques and procedures well known inthe art, such as that described by J. Jacques, et al., “Enantiomers,Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981. Forexample, chiral chromatography with a suitable organic solvent, such asethanol/acetonitrile and Chiralpak AD packing, 20 micron can also beutilized to effect separation of the enantiomers.

In Scheme III, step F, the (+) enantiomer of formula Ia is converted toits pharmaceutically acceptable salt, such as the monohydrochloride,dihydrochloride, monohydrobromide, dihydrobromide, formulaIa/succinate(1:1), formula Ia/succinate 2:1, phosphate, d-tartrate,l-tartrate or maleate salt, in a manner analogous to the proceduredescribed at the end of step D above.

Alternatively, compounds of structure (5) can be prepared following theprocedure described in Scheme IV. All substituents, unless otherwiseindicated, are previously defined. The reagents and starting materialsare readily available to one of ordinary skill in the art.

In Scheme IV, step A, aldehyde (15) is combined with a suitableorganometallic reagent (16) under conditions well known in the art toprovide alcohol (17). Examples of suitable organometallic reagentsinclude Grignard Reagents, alkyl lithium reagents, alkyl zinc reagents,and the like. Grignard Reagents are preferred. For examples of typicalGrignard Reagents and reaction conditions, see J. March, “AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure”, 2^(nd)Edition, McGraw-Hill, pages 836-841 (1977). More specifically, aldehyde(15) is dissolved in a suitable organic solvent, such as tetrahydrofuranor toluene, cooled to about −5° C. and treated with about 1.1 to 1.2equivalents of a Grignard reagent of formula (16) wherein M is MgCl orMgBr. The reaction is allowed to stir for about 0.5 to 2 hours, thenquenched, and alcohol (17) is isolated. For example, the reactionmixture is poured onto ice-cold 1N HCl, the quenched mixture isextracted with a suitable organic solvent, such as toluene, the organicextracts are dried either azeotropically or over a suitable dryingagent, such as anhydrous magnesium sulfate, filtered and concentratedunder vacuum to provide alcohol (17).

In Scheme IV, step B, alcohol (17) is oxidized under standard conditionswell know in the art, such as those described by J. March, “AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure”, 2^(nd)Edition, McGraw-Hill, pages 1082-1084 (1977), to provide ketone (1).[Ketone (1) is the starting material used in Scheme I above.]

For example, alcohol (17) is dissolved in a suitable organic solvent,such as methylene chloride, the solution cooled with a wet ice-acetonebath, and treated with 2.5 to 3.0 equivalents of dimethyl sulfoxide.After stirring for about 30 minutes, the reaction is then treated withabout 1.8 equivalents of P₂O₅. The reaction is allowed to stir for about3 hours and then, preferably, treated over about 30 minutes with about3.5 equivalents of a suitable amine, such as triethylamine. The coolingbath is then removed and the reaction is allowed to stir for about 8 to16 hours. The ketone (1) is then isolated by standard extractiontechniques well known in the art. The above oxidation is also performedusing standard Swern Oxidation conditions which are well known to one ofordinary skill in the art.

In Scheme IV, step C, ketone (1) is treated with a suitable basefollowed by addition of the alkene (18), wherein X is a suitable leavinggroup, to provide compound (19). For example, ketone (1) is combinedwith an excess of alkene (18) in a suitable organic solvent, such astetrahydrofuran, and cooled with a wet ice acetone bath. Examples ofsuitable leaving groups are Cl, Br, I, tosylate, mesylate, and the like.Preferred leaving groups are Cl and Br. About 1.1 equivalents of asuitable base is added and the reaction is allowed to stir for about 2hours at room temperature. Examples of suitable bases are potassiumtert-butoxide, sodium hydride, NaN(Si(CH₃)₃)₂, LDA, KN(Si(CH₃)₃)₂,NaNH₂, sodium ethoxide, sodium methoxide and the like. Potassiumtert-butoxide is the preferred suitable base. The reaction is thenquenched with aqueous acid and compound (19) is isolated by extractionwith a suitable organic solvent, such as heptane. The heptane extractsare washed with sodium bicarbonate, dried over anhydrous magnesiumsulfate, filtered and concentrated under vacuum to provide compound(19).

In Scheme IV, step D, compound (19) is treated with a suitable oxidizingagent to provide aldehyde (3). [Aldehyde (3) is also prepared in SchemeI.] Examples of suitable oxidizing agents are ozone, NaIO₄/Osmiumcatalyst, and the like. Ozone is the preferred oxidizing agent. Examplesof suitable oxidizing reagents and conditions are described by J. March,“Advanced Organic Chemistry: Reactions, Mechanisms, and Structure”,2^(nd) Edition, McGraw-Hill, pages 1090-1096 (1977).

For example, compound (19) is dissolved in a suitable organic solvent,such as methanol, a small amount of Sudan III is added, and the solutionis cooled to about −20° C. Ozone is bubbled into the solution for about4 hours until the pink color turns to a pale yellow color. Then Me₂S isadded to the reaction mixture and the cooling bath is removed.Concentration of the reaction mixture under vacuum provides theintermediate dimethyl acetal of aldehyde (3). This dimethyl acetal isreadily hydrolyzed under standard acidic conditions to provide aldehyde(3). Alternatively, direct acidic work-up of the crude reaction mixtureprovides aldehyde (3). Alternatively, aldehyde (3) can be obtaineddirectly by ozonolysis of (19) in a non-acetal forming solvent, such asmethylene chloride.

In Scheme IV, step E, aldehyde (3) is reductively aminated underconditions analogous to those described above in Scheme III, step D, toprovide compound (5). [Compound 5 is also prepared in Scheme I.]

Scheme V provides an alternative synthesis for the preparation ofcompound (5). All substituents, unless otherwise indicated, arepreviously defined. The reagents and starting materials are readilyavailable to one of ordinary skill in the art.

In Scheme V, step A, aldehyde (3) is condensed with piperidine (4) understandard conditions well known in the art to provide the enamine (20).For example, about 1.05 equivalents of aldehyde (3) dissolved in asuitable organic solvent, such as isopropyl acetate or isopropanol, isadded to neat piperazine (4), free base. Additional organic solvent isadded to produce a slurry and the reaction is stirred for about 1 to 2hours. The enamine (20) is then isolated by standard techniques, such ascollection by filtration.

In Scheme V, step B, the enamine (20) is hydrogenated under conditionswell known by one of ordinary skill in the art to provide compound (5).For example, enamine (20) is combined with a suitable organic solvent,such as isopropyl alcohol and a catalytic amount of 5% palladium oncarbon in a Parr bottle. The mixture is placed under 50 psi of hydrogenand shaken for about 2 days at room temperature. The slurry is thenfiltered to remove catalyst and the filtrate is concentrated to providecompound (5).

The following examples represent typical syntheses of the compounds ofFormula I and formula Ia as described generally above. These examplesare illustrative only and are not intended to limit the invention in anyway. The reagents and starting materials are readily available to one ofordinary skill in the art. As used herein, the following terms have themeanings indicated: “aq” refers to aqueous; “eq” refers to equivalents;“g” refers to grams; “mg” refers to milligrams; “L” refers to liters;“mL” refers to milliliters; “μL” refers to microliters; “mol” refers tomoles; “mmol” refers to millimoles; “psi” refers to pounds per squareinch; “min” refers to minutes; “h” refers to hours; “° C.” refers todegrees Celsius; “TLC” refers to thin layer chromatography; “HPLC”refers to high performance liquid chromatography; “R_(f)” refers toretention factor; “R_(t)” refers to retention time; “δ” refers to partper million down-field from tetramethylsilane; “THF” refers totetrahydrofuran; “DMF” refers to N,N-dimethylformamide; “IPA” refers toisopropyl alcohol; “iPrOAc” refers to isopropyl acetate; “AcOH” refersto acetic acid; “HRMS” refers to high resolution mass spectrometry;“Et₃N” refers to triethylamine; “LDA” refers to lithium diisopropylamide; “RT” refers to room temperature; “SRI” refers to serotoninreuptake inhibitor; “aq” refers to aqueous; and “MTBE” refers totert-butyl methyl ether.

EXAMPLE 1

A. Preparation of 2-(2′-benzoyl-2′-phenyl)ethyl-1,3-dioxolane

To a stirred suspension of sodium hydride (61.25 mmol) in 150 mL ofdimethylformamide at 0° C. under nitrogen was added dropwise a solutionof deoxybenzoin (50.96 mmol) in 150 mL of tetrahydrofuran. The mixturewas stirred at 0° C. for 1 hour and room temperature for 1 hour. To themixture 2-bromomethyl-1,3-dioxolane (60.55 mmol) and catalyst potassiumiodide (6.0 mmol) were added. The mixture was heated to reflux for 13hours. After cooling, diethyl ether (300 mL) and water (300 mL) wereadded. The organic layer was separated and washed with water (150 mL×2).Purification by flash chromatography using hexanes and ethyl acetategave 2-(2′-benzoyl-2′-phenyl)ethyl-1,3-dioxolane (8.18 g; 57%).

B. Preparation of 3-benzoyl-3-phenylpropionaldehyde

To 100 mL of acetone was added2-(2′-benzoyl-2′-phenyl)ethyl-1,3-dioxolane (8.85 mmol) and 100 mL of 2Nhydrochloric acid solution. After the mixture was stirred at roomtemperature for 7 hours, 100 mL of 2N sodium hydroxide was added.Acetone was evaporated and the residue was extracted with diethyl etherand hexanes (1:1, 100 mL×3). The combined organic layer was dried(sodium sulfate), filtered and concentrated. The residue was found to berather pure material (3-benzoyl-3-phenylpropionaldehyde) and thereforeused for next step.

C. Preparation of1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)propyl]piperazine

The 3-benzoyl-3-phenylpropionaldehyde residue obtained from Step B,above, (˜8.85 mmol) was dissolved in 110 mL of methylene chloride. Tothis solution was added 2-methoxyphenylpiperazine (10.61 mmol) andsodium triacetoxyboranehydride, NaBH(OAc)₃, (10.61 mmol). The mixturewas stirred at room temperature for 3 hours. Aqueous workup followed byflash chromatography gave pure product1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)propyl]piperazine (3.48 g)in 95% yield for last two steps. One equivalent of oxalic acid was addedto the free base dissolved in methanol. The solvent was evaporated andthe product was dried under vacuum to form the oxalate salt.

m.p.=161-163° C.;

MS (m/e): 414 (M⁺).

EXAMPLE 2

A. Preparation of cyclohexyl benzyl ketone

To a stirred solution of N-methyl-N-methoxy cyclohexanecarboxamide (7.42mmol) in 30 mL of tetrahydrofuran at 0° C. under nitrogen was added asolution of benzyl magnesium chloride (2.0 M in tetrahydrofuran, 4.5 mL,9.0 mmol). The mixture was stirred at 0° C. for 30 minutes and at roomtemperature for 1 hour. Diethyl ether (50 mL) and water (20 mL) wereadded. The organic layer was separated, dried, filtered, andconcentrated. Purification of the residue by flash chromatography usinghexanes and ethyl acetate gave cyclohexyl benzyl ketone (1.05 g) in 70%yield as oil.

B. Preparation of2-(2′-cyclohexanecarbonyl-2′-phenyl)ethyl-1,3-dioxolane

Following the procedures described in the Example 1, Step A, thereaction of cyclohexyl benzyl ketone (5.09 mmol) and2-bromomethyl-1,3-dioxolane (7.63 mmol) in the presence of sodiumhydride (5.60 mmol) gave2-(2′-cyclohexanecarbonyl-2′-phenyl)ethyl-1,3-dioxolane (0.86 g) in 59%yield.

C. Preparation of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde

Following the procedures described in the Example 1, Step B, thereaction of 2-(2′-cyclohexanecarbonyl-2′-phenyl)ethyl-1,3-dioxolane(2.98 mmol) with 1N hydrochloric acid gave3-cyclohexanecarbonyl-3-phenylpropionaldehyde as a crude product in 100%yield.

D. Preparation of1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine

Following the procedures described in the Example 1, Step C, thereaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.39 mmol)and 2-methoxyphenylpiperazine (1.39 mmol) with sodiumtriacetoxyboranehydride (1.80 mmol) gave pure product1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine(464 mg) in 79% yield. The oxalate salt was prepared as described above.

m.p.=149-151° C.;

MS (m/e): 420 (M⁺).

EXAMPLE 3

Following the procedures described in the Example 1, Step C, thereaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.55 mmol)and 1-(2-pyridyl)piperazine (1.55 mmol) with sodiumtriacetoxyboranehydride (2.0 mmol) gave pure product1-(2-pyridyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine(475 mg) in 78% yield. The oxalate salt was prepared as described above.

m.p.=185-187° C.;

MS (m/e): 391 (M⁺).

EXAMPLE 4

Following the procedures described in the Example 1, Step C, thereaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.02 mmol)and 1-(2-ethoxyphenyl)piperazine (1.13 mmol) with sodiumtriacetoxyboranehydride (1.33 mmol) gave pure product1-(2-ethoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine(270 mg) in 52% yield. To a solution of free base in methanol was addedrequired amount of hydrochloric acid solution in diethyl ether. Thesolvents were removed by reduced pressure, and the product was driedunder vacuum to give dihydrochloric acid salt.

m.p.=180-183° C.;

MS (m/e): 434 (M⁺).

EXAMPLE 5

A. Preparation of 2-(2′-benzoyl-2′-phenyl)propyl-1,3-dioxolane

Following the procedures described in the Example 1, Step A, thereaction of 2-(2′-benzoyl-2′-phenyl)ethyl-1,3-dioxolane (3.54 mmol) andiodomethane (10.62 mmol) in the presence of sodium hydride (4.25 mmol)gave 2-(2′-benzoyl-2′-phenyl)propyl-1,3-dioxolane (0.60 g).

B. Preparation of 3-benzoyl-3-phenylbutyraldehyde

Following the procedures described in the Example 1, Step B, thereaction of 2-(2′-benzoyl-2′-phenyl)propyl-1,3-dioxolane (0.60 g) with3N hydrochloric acid gave 3-benzoyl-3-phenylbutyraldehyde as a crudeproduct (0.32 g).

C. Preparation of1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)butyl]piperazine

Following the procedures described in the Example 1, Step C, thereaction of 3-benzoyl-3-phenylbutyraldehyde (0.32 g) and1-(2-methoxyphenyl)piperazine (0.23 g) with sodiumtriacetoxyboranehydride (0.33 g) gave pure product1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)butyl]piperazine (0.12 g).The oxalate salt was prepared as described above.

m.p.=192-193° C.;

MS (m/e): 428 (M⁺).

EXAMPLE 6

Following the procedures described in the Example 1, Step C, thereaction of 3-cycloheptanecarbonyl-3-phenylpropionaldehyde (2.52 mmol)and 1-(2-methoxyphenyl)piperazine (2.52 mmol) with sodiumtriacetoxyboranehydride (3.28 mmol) gave pure product1-(2-methoxyphenyl)-4-[3-(cycloheptanecarbonyl)-3-(phenyl)propyl]piperazine(770 mg) in 70% yield. The di-hydrochloric acid salt was prepared asdescribed above.

m.p.=193-194° C.;

MS (m/e): 434 (M⁺).

EXAMPLE 7

Following the procedures described in the Example 1, Step C, thereaction of 3-cyclopentanecarbonyl-3-phenylpropionaldehyde (1.36 mmol)and 1-(2-methoxyphenyl)piperazine (1.49 mmol) with sodiumtriacetoxyboranehydride (1.77 mmol) gave pure product1-(2-methoxyphenyl)-4-[3-(cyclopentanecarbonyl)-3-(phenyl)propyl]piperazine(370 mg) in 67% yield. The di-hydrochloric acid salt was prepared asdescribed above.

m.p.=210-212° C.;

MS (m/e): 406 (M⁺).

EXAMPLE 8

To a stirred solution of1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine(0.11 g, 0.20 mmol) in methylene chloride (10 mL) at −78° C. undernitrogen was added Dibal-H™ solution (0.89 mmol). The mixture wasstirred at −78° C. for 1 hour and then slowly warmed to room temperaturefor 16 hours. Workup followed by purification by flash chromatographygave pure1-(2-methoxyphenyl)-4-[4-(cyclohexyl)-4-(hydroxy)-3-(phenyl)butyl]piperazine(0.086 g) in 78% yield. The oxalate salt was prepared as describedabove.

m.p.=100-102° C.;

MS (m/e): 422 (M⁺).

EXAMPLE 9

Preparation of 2-phenyl-1-cyclohexane-ethan-1-one.

Scheme III, step A: A 5 L reaction vessel was charged withtetrahydrofuran (1.05 L) under an atmosphere of nitrogen. The solutionwas cooled with an acetone/ice bath to about −5° C. Liquid dimethylamine(115.9 g, 2.57 mol) was then added through a teflon addition tube. Thecooling bath was removed and the solution was allowed to warm to about15-20° C. Methyl cyclohexanecarboxylate (341.7 g, 2.40 mol) was thenadded resulting in a tea-colored solution. Then benzylmagnesium chloride(2.52 L of a 2.0 M solution in THF, 246 mol) was slowly added at a rateto complete addition in about 1.8 to about 2.2 hours. A cooling bath wasapplied to maintain the temperature of the reaction mixture at about15-20° C. during the addition. After the benzylmagnesium chloridesolution was added, the resulting slurry was stirred at room temperaturefor about 1-2 hours. The reaction mixture was then cooled to less than0° C. Concentrated HCl (709.7 g, 7.2 mol) was combined with water (3.08L) and the solution was cooled to less than 5° C. The dilute acidmixture was added to a 22 L reaction vessel with an ice bath applied tothe vessel. The above-chilled reaction mixture was then slowly pouredinto the chilled dilute acid solution with stirring. An extreme exothermoccurs (Use Caution!). Addition rate of the reaction mixture should becontrolled to maintain the temperature of the quench solution below 45°C. After addition of the reaction mixture to the dilute acid solution,the quenched reaction mixture was cooled to room temperature and the pHwas adjusted to about 6.5 to 7.5 with a sufficient amount ofconcentrated HCl. The quenched reaction mixture was extracted with MTBE(1.71 L). The layers were separated and the organic layer was washedwith a water/MTBE mixture (1.03 L/1.37 L)followed by a second washingwith a water/MTBE mixture (1.03 L/1.03 L). The organic layers werecombined, washed with brine (683 mL), dried over anhydrous magnesiumsulfate (167 g), filtered and concentrated under vacuum. The crude oilwas dried under house vacuum for 5-16 hours to provide crude2-phenyl-1-cyclohexane-ethan-1-one (522.3 g). This crude material wasused in the next reaction without further purification.

Preparation of 1,1-diethoxy-3-phenyl-3-cyclohexanecarbonyl-butane

Scheme III, step B; 2-Phenyl-1-cyclohexane-ethan-1-one (8.26 g, 40.8mmol) was combined with DMSO (45 mL) in a 3-necked, 250 mL round bottomflask equipped with a magnetic stir bar, thermocouple-digitalthermometer unit and an addition funnel. To the stirring solution wasadded potassium tert-butoxide (5.04 g, 44.9 mmol). A 16° C. exotherm wasobserved and the yellow solution became dark brown. The reaction mixturewas stirred for an additional 15 minutes after addition was complete,and then bromoacetaldehyde diethyl acetal (8.26 g, 41.9 mmol) was addeddropwise via the addition funnel over approximately 10 minutes. Thereaction mixture was then heated at 50° C. for 2 to 2.5 hours duringwhich the reaction mixture became yellow. The reaction mixture was thencooled with an ice/water bath to about 9.5° C. and potassiumtert-butoxide (10.07 g, 89.7 mmol) was added resulting in an exothermicreaction and change in color from yellow to brown. With the cooling bathstill in place, the reaction mixture was stirred for an additional 15minutes followed by dropwise addition of iodomethane (10.26 g, 72.3mmol, neat). The temperature of the reaction mixture was maintained ator below 21° C. Any exotherm during the iodomethane addition should bemaintained below 41-43° C., which is the boiling point of iodomethane.After addition was complete, the reaction mixture was allowed to stirfor 1 to 4 hours at room temperature. The reaction mixture was thenpartitioned between MTBE (100 mL) and water (100 mL). The organic phasewas washed with water (3×50 mL), brine (50 mL), dried over anhydrousmagnesium sulfate, suction filtered and concentrated under vacuum toprovide crude 1,1-diethoxy-3-phenyl-3-cyclohexanecarbonyl-butane (13.6g) as a yellow oil. This crude material was used in the next reactionwithout further purification.

Preparation of 1-cyclohexyl-2-phenyl-butan-1-one-4-al

Scheme III, step C; 1,1-Diethoxy-3-phenyl-3-cyclohexanecarbonyl-butane(74.4 g, 224 mmol) was dissolved in acetone (800 mL) followed byaddition of 3.0 N HCl (800 mL). The reaction mixture was stirred for onehour at room temperature. It was then concentrated under vacuum to lessthan ½ its original volume and then extracted with methylene chloride(800 mL). The organic extract was then washed with brine (300 mL), driedover anhydrous magnesium sulfate, suction filtered and concentratedunder vacuum to provide crude 3-phenyl-3-cyclohexanecarbonyl-butan-1-al(57.8 g). Alternatively, the dried and filtered methylene chloridesolution can be used directly in the next step without concentration.

Preparation of the final title compound,1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine

Scheme III, step D; 3-Phenyl-3-cyclohexanecarbonyl-butan-1-al (57.8 g,224 mmol) was dissolved in methylene chloride (1650 mL) followed byaddition of 1-(2-methoxyphenyl)piperazine hydrochloride (56.3 g, 246mmol). Acetic acid (41 mL) may optionally be added to turn the slurryinto a solution. To the stirred solution, sodium triacetoxyborohydride(60.3 g, 284 mmol) was slowly added. A slight exotherm resulted and aslurry was produced. The reaction mixture was stirred for an additional3 hours at room temperature. The reaction was then quenched by additionof 2.0 N sodium hydroxide (1050 mL) producing a pH of about 10 for thequenched reaction mixture. The mixture was then extracted with methylenechloride (2 times, 1 L and 300 mL). The organic extracts were combined,washed successively with 1.0 N HCl (600 mL), 1.0 N sodium hydroxide (600mL), brine (600 mL), dried over anhydrous magnesium sulfate, filteredand concentrated under vacuum to provide the final title compound as athick oil;

UV (MeOH): λ_(max)=243 nm, ε₂₄₃=7110; λ_(max)=281 nm, ε₂₈₁=3200

IR (CDCl₃, cm⁻¹) 2937, 2856, 2836, 1698, 1499, 1451, 1377, 1316, 1242,1029

¹H NMR (300 MHz, DMSO) δ7.75 (2H, m), 7.55 (2H, m), 6.93 (3H, m), 6.85(2H, m), 3.75 (3H, s), 2.90 (4H, m), 2.43 (4H, m), 2.08 (5H, m), 1.5(10H, m), 1.05 (3H, m)

¹³C NMR (300 MHz, DMSO) δ214.18, 151.94, 141.25, 141.23, 128.45, 126.85,126.74, 122.22, 120.79,. 117.81, 111.97, 55.28, 54.54, 53.67, 53.13,50.01, 45.30, 33.75, 30.44, 30.12, 25.21, 24.98, 24.93, 19.94.

Anal. Calcd for C₂₈H₃₈N₂O₂: C, 77.38; H, 8.81; N, 6.45. Found: C, 76.44;H, 8.89; N, 6.01.

Preparation of1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinemaleate

1-(2-Methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine(prepared directly above) was dissolved in warm methanol (50 mL)followed by addition of maleic acid (26.8 g) and MTBE (200 mL). Thismixture was concentrated to a paste and then redissolved by addition ofmethanol (approximately 15 mL) and MTBE (200 mL). The mixture was seededand an additional amount of MTBE (300 mL) was added once crystallizationwas initiated. The mixture was suction filtered, and the solid rinsedwith MTBE and vacuum dried for 5 hours at 40° C. to provide the titlecompound (122 g).

In addition, one of ordinary skill in the art could prepare the titlecompound,1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine,in a manner analogous to the procedures described above, from3-cyclohexanecarbonyl-3-phenylbutyraldehyde and1-(2-methoxyphenyl)piperazine as described generally in Scheme V.

Preparation of1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine2HCl

The title compound is prepared by one of ordinary skill in the art, in amanner analogous to preparation of the above maleate salt, from the freebase and hydrochloric acid to provide a white solid; mp(DSC)=192.81° C.

Preparation of(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazineand(−)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine

Scheme III, step E:

Materials:

Chiralpak AD Bulk packing, 20 micron

Acetonitrile

3A alcohol

Prochrom 8 cm column

Prochrom LC-80 system/collection system

Column Preparation: A ProChem LC-80 automated system with an 8×19 cmProchrom column (ProChem, 5622 West 73^(rd) Street, Indianapolis, Ind.46278)is slurry packed using approximately 500 g Chiralpak AD (ChiralTechnologies, 730 Springdale Drive, Exton, Pa. 19341) in propanol (1 L).An eluent containing approximately 5% 3A alcohol in acetonitrile wasprepared. Column flow rate was 155 mL/min and the detector was set at280 nm. The racemic1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(methyl)-3(phenyl)propyl]piperazine(25 g) was dissolved in acetonitrile (50 mL). Approximately 3 g of thissolution was weighed into a flask and diluted with acetonitrile (50 mL).This solution was then pumped onto the column to begin separation of the(+) and (−) enantiomers of1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine.Fractions were then collected with the (−) enantiomer eluting first.Approximate total cycle time is 15 minutes.

The enantiomeric excess of the two separated isomers was determinedunder the following conditions:

Column: 46×15 cm Chiralcel OH—H

Eluent: 3% ethanol in Heptane containing 0.2% dimethylamine

Flow rate: 0.6 mL/min

Temperature: ambient

uv: 280 nm

%ee for the (−) enantiomer 96.4%.

%ee for the (+) enantiomer 96.6%.

Preparation of(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinedihydrochloride

Scheme III, step F:(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine(15.0 g, 34.5 mmol, prepared above) was diluted with methanol (40 mL).To this solution was added HCl (9.58 g of a 26.3% solution in methanol,69.0 mmol). The mixture began to form gelatinous-looking crystals andset up solid within minutes. To this mixture was added with vigorousstirring, diethyl ether (100 mL). The white solid was collected bysuction filtration and then dried under vacuum at 45° C. for two days toprovide the title compound (13.4 g, 76%) as a white solid;mp(DSC)=195.58° C.

IR (CDCl₃, cm⁻¹) 2976, 2939, 1700, 1502, 1462, 1451, 1267, 1243, 1021;

¹H NMR (300 MHz, DMSO) δ7.40 (2H, m), 73.1 (3H, m) 7.03 (3H, M) 6.90(1H, m) 3.78 (3H, s) 3.49 (4H, m) 3.16 (5H, m) 2.64 (1H, m) 2.40 (3H, m)1.56 (3H, s) 1.46 (4H, m) 1.11 (5H, m) 0.86 (1H, m);

¹³C NMR (300 MHz, DMSO) δ213.46, 151.84, 139.56, 138.12, 128.72, 127.37,126.86, 124.29, 120.85, 118.71, 112.29, 55.48, 54.06, 52.20, 50.78,50.57, 46.93, 45.14, 30.31, 30.16, 25.15, 24.91, 24.89, 19.15;

HRMS calcd for C₂₈H₃₉N₂O₂ (MH⁺) 435.3012, found 435.3018.

α[α]²⁵ _(D)=+76.530° (c=1, MeOH), ee 99.3% (Chiral HPLC).

Preparation of(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinemonohydrochloride

Scheme III, step F:(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine(6.05 g, 13.9 mmol) was diluted with MTBE (120 mL) followed by additionof HCl (2.2 M solution in isopropanol, 6.3 mL, 13.9 mmol, prepared from0.80 g of HCl gas in 10 mL of isopropanol). The mixture formed anoil/solid mixture which upon further stirring yielded a uniformlycrystalline material. The mixture was suction-filtered and rinsed withMTBE to provide a white solid which was dried under vacuum at 45° C.(5.74 g, 96.2% ee).

(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinemonohydrochloride can be prepared in an analogous manner as above froman equivalent of concentrated aqueous HCl in place of the gaseous HCl.

Alternative preparation of1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine

Preparation of 1-Cyclohexyl-2-phenylpropanol

Scheme IV, step A: To a solution of cyclohexylmagnesium chloride (50mmol) in 25 mL of Et₂O and 40 mL of THF at −5° C. was added a solutionof 2-phenylpropanaldehyde (5.36 g, 40 mmol) in 10 mL of THF. Thereaction mixture exothermed to 5° C. After stirring at room temperaturefor 75 min, the solution was poured onto ice cold 1 N HCl, extractedwith toluene, dried over MgSO₄, and concentrated to give the titlecompound as a colorless oil (6.15 g, 70%):

¹H NMR (d⁶-DMSO): δ7.23-7.30 (m, 2H, phenyl CH), 7.15-7.22 (m, 3H,phenyl CH), 4.17-4.51 (br s, 1H, —OH), 3.23-3.33 (m, 1H, R₂CHOH), 2.78(dq, J=7.0 Hz, J=7.1 Hz, 1H, —CH(CH₃)Ph), 1.23-1.83 (m, 6H, cyclohexylCH), 1.20 (d, J=6.9 Hz, 3H, —CH (CH ₃)Ph), 0.88-1.18 (m, 5H, cyclohexylCH).

Preparation of Cyclohexyl 1-phenylethyl ketone

Scheme IV, step B: DMSO (118 mL, 1.6674 mol) was added dropwise to asolution of 126.42 g (0.579 mol) of 1-cyclohexyl-2-phenylpropanol in1737 mL of CH₂Cl₂ (cooled in a wet ice acetone bath). After 29 min,147.93 g (1.0422 mol) of P₂O₅ was added. After 11 min, the cooling bathwas removed. An aliquot quenched with Et₃N showed complete reactionwithin 3 h at RT. The reaction mixture was cooled in a wet ice acetonebath. Et₃N (282 mL, 2.0265 mol) was added dropwise to the cooledreaction mixture over a 30 min period. The cooling bath was removed andthe mixture was stirred overnight at RT. The reaction mixture wasquenched by dropwise addition of 500 mL of 3 N HCl (aq) (pH=0). Aftershaking in separatory funnel, the aqueous phase was removed. The organicphase was washed with 500 mL of 3 N HCl (aq) (pH=0), washed twice with 1L of 10% K₂CO₃ (aq) (pH=12;12), washed three times with 500 mL of NaOCl(aq) solution, washed with 1 L of water, washed with 1 L of 25% NaCl(aq), dried over MgSO₄, gravity filtered and concentrated under vacuumwith dry ice trap to collect Me₂S. An amber oil of the title compound(107.01 g, 85.437%) was obtained;

¹H NMR (d⁶-DMSO): δ7.30-7.37 (m, 2H, phenyl CH), 7.21-7.28 (m, 3H,phenyl CH), 4.08 (q, J=6.9 Hz, 1H, —CH(CH₃)Ph), 2.40-2.49 (m, 1H,cyclohexyl CH), 1.82-1.84 (m, 1H, cyclohexyl —CH₂), 1.67-1.69 (m, 1H,cyclohexyl —CH₂), 1.52-1.63 (m, 1H, cyclohexyl —CH₂), 1.34-1.43 (m, 1H,cyclohexyl —CH₂), 1.26 (d, J=6.9 Hz, 3H, —CH(CH ₃)Ph), 1.01-1.24 (m, 4H,cyclohexyl —CH₂).

Preparation of 2-phenyl-2-methyl-4-pentenoyl cyclohexane

Scheme IV, step C; A solution of 31.39 g (0.2797 mol) of t-BuOK in 100mL of THF was added dropwise to a solution of 55.00 g (0.2543 mol) ofcyclohexyl 1-phenylethyl ketone and 26.4 mL (0.3052 mol) of allylbromide in 136 mL of THF (cooled in a wet ice acetone bath). THFwashings (16 mL) were added to the reaction mixture. The cooling bathwas removed after addition. After reaction completion (2 h), thereaction mixture was quenched with 300 mL of 1 N HCl (pH=0) andextracted with 300 mL of heptane. The heptane extract was washed with10% NaHCO₃ (aq) (pH=9), dried over MgSO₄, gravity filtered andconcentrated under vacuum to afford 59.70 g (91.58%) of title compoundas an amber oil:

¹H NMR (d⁶-DMSO): δ7.32-7.42 (m, 2H, phenyl CH), 7.24-7.31 (m, 3H,phenyl CH), 5.34-5.47 (m, 1H, —CH═CH₂), 5.02 (dd, J=17.1 Hz, J=2.1 Hz,1H, —CH═CH—H (trans)), 4.97 (ddd, J=10.2 Hz, J=2.2 Hz, J=1.0 Hz, 1H,—CH═CH—H (cis, W-coupling)), 2.66 (ddd, J=14.2 Hz, J=6.9 Hz, J=1.0 Hz,1H, —CH ₂CH═CH₂), 2.59 (ddd, J=14.2 Hz, J=7.3 Hz, J=1.0 Hz, 1H, —CH₂CH═CH₂), 2.38-2.49 (m, 1H, cyclohexyl CH), 1.48-1.69 (m, 4H, cyclohexyl—CH ₂), 1.46 (s, 3H, —CH(CH ₃)Ph), 1.36-1.44 (m, 1H, cyclohexyl —CH ₂),0.82-1.36 (m, 5H, cyclohexyl —CH ₂).

Preparation of 4-Cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde

Scheme IV, step D: Ozone was bubbled through a cloudy mixture of 56.50 g(0.2204 mol) of 2-phenyl-2-methyl-4-pentenoyl cyclohexane and a smallamount (˜10 mg) of Sudan III in 220 mL of MeOH (cooled in a dry iceacetone bath at −20° C.) for 4 h until pink color turned to pale yellowcolor. After all of the olefin was consumed, Me₂S (50 mL) was added toreaction mixture. The cooling bath was removed. The exotherm rose to 38°C. and mixture was cooled in cooling bath until there was no exotherm.Then the cooling bath was removed and the mixture was stirred overnight.The reaction solution was concentrated under vacuum with dry ice trap tocollect excess Me₂S to afford 83.65 g of crude4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde dimethyl acetal as apink oil:

¹H NMR (d⁶-DMSO): δ7.34-7.39 (m, 2H, phenyl CH), 7.24-7.30 (m, 3H,phenyl CH), 3.99 (dd, J=4.2 Hz, J=5.9 Hz, 1H, CH(OCH₃)₂), 3.14 (s, 3H,CH(OCH ₃)₂), 3.06 (s, 3H, CH(OCH ₃)₂), 2.34-2.43 (m, 1H, cyclohexyl CH),2.10-2.20 (m, 2H, —CH ₂CH(OCH ₃)₂), 1.55-1.67 (m, 1H, cyclohexyl —CH ₂),1.53 (s, 3H, R₂C(CH₃)Ph), 0.80-1.52 (m, 9H, cyclohexyl —CH ₂).

To a solution of 82.65 g (66.29 g, 0.2177 mol) of4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde dimethyl acetal in 539mL of acetone was added 539 mL of 3 N HCl (aq) at RT. After reactioncompletion (2 h), the mixture was concentrated to 426.5 g (or 1/3volume) of residue (RT-40° C). The residue contained mostly water (pH=0)and was extracted twice with 300 mL of MTBE. The MTBE extract was washedwith 300 mL of 25% NaCl (aq), dried over MgSO₄, gravity filtered andconcentrated to afford 54.92 g (97.65%) of title compound as a pink oil:

¹H NMR (d⁶-DMSO): δ9.54 (t, J=2.0 Hz, 1H, —CHO), 7.36-7.45 (m, 2H,phenyl CH), 7.28-7.35 (m, 3H, phenyl CH), 2.95 (dd, J=16.6 Hz, J=1.9 Hz,1H, CH ₂CHO), 2.85 (dd, J=16.6 Hz, J=1.7 Hz, 1H, CH ₂CHO), 2.41-2.49 (m,1H, cyclohexyl CH), 1.72 (s, 3H, R₂C(CH₃)Ph), 0.85-1.66 (m, 10H,cyclohexyl —CH ₂).

Preparation of final title compound1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine.

Scheme IV, step E: To a slurry of 13.72 g (0.05310 mol) of4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde and 11.57 g (0.05058mol) of 1-(2′-methoxyphenyl)piperazine hydrochloride in 391 mL of CH₂Cl₂was added 9.7 mL of AcOH to make the reaction mixture homogeneous. Tothe reaction solution was added slowly 14.63 g (0.06904 mol) ofNaBH(OAc)₃. After stirring over 4 days (reaction should be completewithin 2-5 h), 200 mL of 1N HCl (aq) was added to quench reactionmixture (pH=1). The mixture was extracted with 200 mL of CH₂Cl₂. TheCH₂Cl₂ extract was washed again with 200 mL of 1N HCl (aq) (pH=1). BothHCl (aq) washes were combined and saved. The organic extract was washedwith 200 mL of 1N NaOH (aq) (pH=14). An emulsion formed and was brokenup by addition of 100 mL of water and 100 mL of MTBE. The organic phasewas washed again with 200 mL of 1N NaOH (aq) (pH=14) and washed with 200mL of 25% NaCl (aq), dried over MgSO₄, gravity filtered and concentratedto afford 22.74 g of crude title compound as an amber oil. HPLC analysisagainst pure standard showed that crude product oil has 13.66 g (61.71%)of title compound.

To the combined HCl wash was added 28.44 g of NaOH (s) to make mixturebasic (pH=14). The cloudy mixture was extracted twice with 100 mL ofCH₂Cl₂. The CH₂Cl₂ extracts were combined, washed with 25% NaCl (aq),dried over MgSO₄, gravity filtered and concentrated to afford 1.86 g ofamber oil residue that contained 0.096 g (total=62.15%) of titlecompound and 1.05 g (10.8% recovery) of 1-(2′-methoxyphenyl)piperazine.

¹H NMR (d⁶-DMSO): δ7.35-7.43 (m, 2CH, phenyl CH), 7.26-7.32 (m, 3H,phenyl CH), 6.89-6.96 (m, 2H, phenyl CH), 6.83-6.88 (m, 2H, phenyl CH),3.76 (s, 3H, OCH ₃), 2.80-3.03 (m, 4H, piperazine CH ₂), 2.34-2.49 (m,4H, piperazine CH ₂), 1.91-2.24 (m, 4H), 1.52-1.62 (m, 2H, cyclohexyl CH₂), 1.51 (s, 3H, R₂C(CH₃)Ph), 1.34-1.48 (m, 2H, cyclohexyl —CH ₂),1.13-1.27 (m, 4H, cyclohexyl —CH ₂), 1.00-1.10 (m, 2H, cyclohexyl —CH₂), 0.83-1.00 (m, 1H, cyclohexyl —CH ₂).

Alternative preparation of final title compound

Preparation of enamine

Scheme V, step A: To a solution of 25.00 g (0.1093 mol) of1-(2′-methoxyphenyl)piperazine hydrochloride in 42 mL of water was added14.5 mL (0.109 mol) of concentrated (29.4%) NH₄OH (aq) (pH=9). Themixture was extracted twice with 250 mL of 1:1 (v/v) of THF:toluene. Theorganic extracts were combined, dried over MgSO₄, gravity filtered andconcentrated to afford 20.17 g (96.00%) of1-(2′-methoxyphenyl)piperazine as a pale green oil:

¹H NMR (d⁶-DMSO): d 6.90-6.97 (m, 2H, phenyl CH), 6.83-6.90 (m, 3H,phenyl CH), 3.77 (s, 3H, OCH₃), 2.77-2.91 (m, 8H, piperazine CH ₂),2.49-2.53 (m, 1H, NH). A solution of 9.55 g (0.0370 mol) of4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde in 10 mL of iPrOAc wasadded to 6.77 g (0.0352 mol) of neat 1-(2′-methoxyphenyl)piperazine. Themixture turned turbid, and then turned to a solid mass when 10 mL ofiPrOAc was added. The solid was slurried with 45 mL of iPrOAc. After 1.5h, reaction was complete. The solid was vacuum filtered and washed with10 mL of iPrOAc and air dried to afford 9.81 g (64.4%) of pure enamineas an off-white powder. The filtrate was concentrated to afford 6.40 gof crude enamine;

¹H NMR (d⁶-DMSO): δ7.31-7.43 (m, 2H, phenyl CH), 7.20-7.31 (m, 3H,phenyl CH), 6.82-7.04 (m, 4H, phenyl CH), 6.06 (d, J=14.2 Hz, 1H,CR₃CH═CHNR₂(trans)), 4.98 (d, J=14.2 Hz, 1H, CR₃CH═CH NR₂(trans)), 3.80(s, 3H, OCH ₃), 2.93-3.15 (m, 8H, piperazine CH ₂), 2.38-2.49 (m, 1H,cyclohexyl CH), 1.59-1.72 (m, 2H, cyclohexyl CH ₂), 1.47-1.59 (m, 2H,cyclohexyl —CH ₂), 1.40 (s, 3H, R₂C(CH₃)Ph), 1.21-1.34 (m, 3H,cyclohexyl —CH ₂), 1.03-1.21 (m, 2H, cyclohexyl —CH ₂), 0.83-1.03 (m,1H, cyclohexyl —CH₂).

Preparation of final title compound

Scheme V, step B: To 5.35 g (0.00101 mol) of 5% Pd/C in a 500 mL Parrbottle chilled in an ice bath was added 8.68 g (0.0201 mol) ofabove-formed enamine. To the solid mixture was added 40 mL of IPA cooledin a freezer (−22° C.). H₂ was introduced at 50 psi and mixture wasshaken for 2 day at RT to complete reaction. The black slurry was vacuumfiltered and concentrated to afford 8.70 g of a colorless oil. The Pd/Ccatalyst was washed with 50 mL of IPA with stirring. The black slurrywas vacuum filtered. The filtrate was combined with 8.70 g of residueand concentrated to afford 10.03 g of the final title compound as acolorless oil.

Additional compounds included with the scope of the present invention,which can be prepared by one of ordinary skill in the art in a manneranalogous to the procedures described above, are as follows:

10)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinedihydrobromide;

11)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinemonohydrobromide;

12)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinesuccinate, 1:1;

13)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinesuccinate, 2:1;

14)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinephosphate;

15)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazined-tartrate;

16)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinel-tartrate;

17)(+)-1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazinemaleate;

Serotonin 1A Receptor Activity

The compounds of the present invention are selective antagonists at theserotonin 1A receptor. Previously known compounds with 1A receptoractivity typically have the disadvantage of possessing other centralnervous system activities as well. It is now well understood bypharmacologists and physicians that pharmaceuticals which have a singlephysiological activity, or which are much more active in the desiredactivity than in their other activities, are much more desirable fortherapy than are compounds (pindolol for example) which have multipleactivities at about the same dose.

Many other known serotonin receptor 1A antagonists typically haveα-adrenergic, β-adrenergic or dopamine-2 activity as well, and aretherefore nonselective for 1A activity.

The 5-HT_(1A) receptor binding potency of the present compounds has beenmeasured by a modification of the binding assay described by Taylor, etal. (J. Pharmacol. Exp. Ther., 236, 118-125, 1986); and Wong, et al.,Pharm. Biochem. Behav., 46, 173-77 (1993). Membranes for the bindingassay were prepared from male Sprague-Dawley rats (150-250 g). Theanimals were killed by decapitation, and the brains were rapidly chilledand dissected to obtain the hippocampi. Membranes from the hippocampiwere either prepared that day, or the hippocampi were stored frozen(−70°) until the day of preparation. The membranes were prepared byhomogenizing the tissue in 40 volumes of ice-cold Tris-Hydrochloric acidbuffer (50 mM, pH 7.4 at 22°) using a homogenizer for 15 seconds, andthe homogenate was centrifuged at 39800×g for 10 minutes. The resultingpellet was then resuspended in the same buffer, and the centrifugationand resuspension process was repeated three additional times to wash themembranes. Between the second and third washes the resuspended membraneswere incubated for 10 minutes at 37° to facilitate the removal ofendogenous ligands. The final pellet was resuspended in 67 mMTris-Hydrochloric acid, pH 7.4, to a concentration of 2 mg of tissueoriginal wet weight/200 μl. This homogenate was stored frozen (−70°)until the day of the binding assay. Each tube for the binding assay hada final volume of 800 μl and contained the following: Tris-Hydrochloricacid (50 mM), pargyline (10 μM), CaCl₂ (3 mM), [³H]8-OH-DPAT (1.0 nM),appropriate dilutions of the drugs of interest, and membraneresuspension equivalent to 2 mg of original tissue wet weight, for afinal pH of 7.4. The assay tubes were incubated for either 10 minutes or15 minutes at 37°, and the contents were then rapidly filtered throughGF/B filters (pretreated with 0.5% polyethylenimine), followed by fourone-ml washes with ice-cold buffer. The radioactivity trapped by thefilters was quantitated by liquid scintillation spectrometry, andspecific [³H]8-OH-DPAT binding to the 5-HT_(1A) sites was defined as thedifference between [³H]8-OH-DPAT bound in the presence and absence of 10μM 5-HT.

IC₅₀ values, i.e., the concentration required to inhibit 50% of thebinding, were determined from 12-point competition curves usingnonlinear regression (SYSTAT, SYSTAT, Inc., Evanston, Ill.). IC₅₀ valueswere converted to K_(i) values using the Cheng-Prusoff equation(Biochem. Pharmacol., 22, 3099-3108 (1973). All experiments wereperformed in triplicate.

Additional binding assays of some of the present compounds have beencarried out by an assay method which uses a cloned cell line whichexpresses the serotonin 1A receptor, rather than the hippocampalmembranes. Such cloned cell lines have been described by Fargin, et al.,J.Bio. Chem., 264, 14848-14852 (1989), Aune, et al., J. Immunology, 151,1175-1183 (1993), and Raymond, et al., Naunyn-Schmiedeberg's Arch.Pharmacol., 346, 127-137 (1992). Results from the cell line assay aresubstantially in agreement with results from the hippocampal membraneassay. 5HT_(1a) antagonist, in vivo tests

a) ⁵HT_(1a) Antagonism Subcutaneous Test

Compounds were tested over a range of subcutaneous doses for activity inblocking the 8-OH-DPAT induced behaviors and hypothermia. Lower lipretraction (LLR) and flat body posture (FBP) were recorded in maleSprague Dawley rats (˜250 grams from Harlan Sprague Dawley). Both LLRand FBP were measured on a scale of 0-3 (Wolff et al, 1997). In the LLRbehavioral assay, “0” indicated normal lip position; “1” indicated aslight separation of the lips; “2” indicated that the lips were openwith some teeth visible; “3” indicated that the lips were fully openwith all the front teeth exposed. In the FBP assay, a score of “0”indicated normal body posture; “1” indicated that the stomach was on thefloor with the back in its normal rounded position; “2” indicated thatthe stomach was on the floor with the back straightened and rising fromthe shoulders to the hips; “3” indicated that the stomach was pressedinto the floor and the back was flattened with the shoulders and hipseven. Core body temperature was recorded by rectal probe inserted 5.0 cmimmediately after the behavioral measures. Rats were injectedsubcutaneous with compound (at 0, 0.3, 1.0 and 3.0 mg/kg) 35 minutesbefore scoring and the 8-OH-DPAT (0.1 mg/kg subcutaneous) was injected20 minutes before scoring.

b) 5HT_(1a) Agonist Subcutaneous Test

The compounds were also tested at a high dose of 10 mg/kg subcutaneousalone to see if they induced 5HT_(1a) agonist-like hypothermia.

The potent serotonin 1A receptor activity of the present compounds givesthem a number of pharmaceutical and therapeutic applications. One ofthose applications is a method of assisting people who are dependent onthe use of tobacco or nicotine to break the habit.

Tobacco or Nicotine Withdrawal

It is well known that the chronic administration of nicotine results intolerance and, eventually, dependence. The use of tobacco has becomeextremely widespread in all countries, despite the well known adverseeffects of the use of tobacco in all its forms. Thus, it is clear thattobacco use is extremely habit-forming, if not addictive, and that itsuse provides sensations to the user which are pleasant and welcome, eventhough the user is fully aware of the drastic long term ill effects ofits use.

Rather recently, vigorous campaigns against the use of tobacco havetaken place, and it is now common knowledge that the cessation ofsmoking brings with it numerous unpleasant withdrawal symptoms, whichinclude irritability, anxiety, restlessness, lack of concentration,lightheadedness, insomnia, tremor, increased hunger and weight gain,and, of course, a craving for tobacco.

At the present time, probably the most widely used therapy to assist thecessation of tobacco use is nicotine replacement, by the use of nicotinechewing gum or nicotine-providing transdermal patches. It is widelyknown, however, that nicotine replacement is less effective withouthabit-modifying psychological treatment and training.

The method of the present invention is broadly useful in assistingpersons who want to cease or reduce their use of tobacco or nicotine.Most commonly, the form of tobacco use is smoking, most commonly thesmoking of cigarettes. The present invention is also helpful, however,in assisting in breaking the habit of all types of tobacco smoking, aswell as the use of snuff, chewing tobacco, etc. The present method isalso helpful to those who have replaced, or partially replaced, theiruse of tobacco with the use of nicotine replacement therapy. Thus, suchpatients can be assisted to reduce and even eliminate entirely theirdependence on nicotine in all forms.

It will be understood that the present invention is useful forpreventing or alleviating the withdrawal symptoms which afflict patientswho are trying to eliminate or reduce their use of tobacco or nicotine.The common withdrawal symptoms of such people include, at least,irritability, anxiety, restlessness, lack of concentration, insomnia,nervous tremor, increased hunger and weight gain, light-headedness, andthe craving for tobacco or nicotine. The prevention or alleviation ofsuch symptoms, when they are caused by or occur in conjunction withceasing or reducing the patient's use of tobacco or nicotine is adesired result of the present invention and an important aspect of it.

The present invention is carried out by administering an effectiveamount of a compound of Formula I or formula Ia to a patient who is inneed of or carrying out a reduction or cessation of tobacco or nicotineuse.

As used herein, the term “patient” refers to a warm-blooded animal, suchas a mammal. Included within the term “patient” are humans, dogs, rats,mice and the like. It is understood that the preferred patient is ahuman.

An effective amount of a compound of Formula I or formula Ia, is theamount, or dose, of the compound which provides the desired effect inthe patient under diagnosis or treatment. The dose of compound ofFormula I or formula Ia to be administered, is effective over a widedosage range, in general, it is from about 1 to about 200 mg/day; asusual, the daily dose may be administered in a single bolus, or individed doses, depending on the judgment of the physician in charge ofthe case. A more preferred range of doses is from about 5 to about 100mg/day; other dosage ranges which may be preferred in certaincircumstances are from about 10 to about 50 mg/day; from about 5 toabout 50 mg/day; from about 10 to about 25 mg/day; and a particularlyreferred range is from about 20 to about 25 mg/day. It will beunderstood that the dose for a given patient is always to be set by thejudgment of the attending physician, and that the dose is subject tomodification based on the size of the patient, the lean or fat nature ofthe patient, the characteristics of the particular compound chosen, theintensity of the patient's tobacco habit, the intensity of the patient'swithdrawal symptoms, and psychological factors which may affect thepatient's physiological responses.

The effect of the compounds in alleviating the symptoms of nicotinewithdrawal was evaluated in rats by an auditory startle test, which wascarried out as follows.

Procedures for Nicotine Withdrawal Studies

Animals: Male Long Evans rats were individually housed in a controlledenvironment on a 12 hour light-dark cycle and were given free access tofood (Purina Rodent Chow) and water. All treatment groups contained 8-10rats.

Chronic Nicotine Treatment: Rats were anesthetized with halothane andAlzet™ osmotic minipumps (Alza Corporation, Palo Alto, Calif., Model2ML2) were implanted subcutaneously. Nicotine ditartrate was dissolvedin physiological saline. Pumps were filled with either nicotineditartrate (6 mg/kg base/day) or physiological saline. Twelve daysfollowing implantation of pumps, rats were anesthetized with halothaneand the pumps were removed.

Auditory Startle Response: The sensory motor reactions [auditory startleresponse (peak amplitude Vmax)] of individual rats was recorded usingSan Diego Instruments startle chambers (San Diego, Calif.). Startlesessions consisted of a 5-minute adaptation period at a background noiselevel of 70±3 dBA immediately followed by 25 presentations of auditorystimuli (120±2 dBA noise, 50 ms duration) presented at 8-secondintervals. Peak startle amplitudes were then averaged for all 25presentations of stimuli for each session. Auditory startle respondingwas evaluated daily at 24 hour intervals on days 1-4 following nicotinewithdrawal.

Combination with Reuptake Inhibitors

A further application of the compounds of Formula I or formula Ia istheir use in combination with a serotonin reuptake inhibitor to furtherpotentiate the action of those drugs by increasing the availability ofserotonin, as well as norepinephrine and dopamine, in the brain ofpatients to whom the drug combination is administered. Typical andappropriate serotonin reuptake inhibitors (SRI) are fluoxetine,duloxetine, venlafaxine, milnacipran, citalopram, fluvoxamine andparoxetine. Accordingly, the present invention provides a method forpotentiating the action of a serotonin reuptake inhibitor, particularlyone of the group consisting of fluoxetine, duloxetine, venlafaxine,milnacipran, citalopram, fluvoxamine and paroxetine, in increasing theavailability of serotonin, norepinephrine and dopamine in the brain,comprising administering said serotonin reuptake inhibitor incombination with a compound of Formula I or formula Ia. The inventionalso provides pharmaceutical compositions which comprise a serotoninreuptake inhibitor in combination with a compound of Formula I orformula Ia, and a method of treating a pathological condition which iscreated by or is dependent upon decreased availability of serotonin,dopamine or norepinephrine, which method comprises administering thesame adjunctive therapy to a patient in need of such treatment.

Fluoxetine, N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine,is marketed in the hydrochloride salt form, and as the racemic mixtureof its two enantiomers. U. S. Pat. No. 4,314,081 is an early referenceon the compound. Robertson, et al., J. Med. Chem., 31, 1412 (1988),taught the separation of the R and S enantiomers of fluoxetine andshowed that their activity as serotonin uptake inhibitors is similar toeach other. In this document, the word “fluoxetine” will be used to meanany acid addition salt or the free base, and to include either theracemic mixture or either of the R and S enantiomers.

Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, isusually administered as the hydrochloride salt and is the (+)enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which showsits high potency. The word “duloxetine” will be used here to refer toany acid addition salt or the free base of the molecule.

Venlafaxine is known in the literature, and its method of synthesis andits activity as an inhibitor of serotonin and norepinephrine uptake aretaught by U.S. Pat. No. 4,761,501. Venlafaxine is identified as compoundA in that patent.

Milnacipran (N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide)is taught by U.S. Pat. No. 4,478,836, which prepared milnacipran as itsExample 4. The patent describes its compounds as antidepressants. Moret,et al., Neuropharmacology 24, 1211-19 (1985), describe itspharmacological activities.

Citalopram,1-[3-(dimethylamino)propyl]-1(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile,is disclosed in U.S. Pat. No. 4,136,193 as a serotonin reuptakeinhibitor. Its pharmacology was disclosed by Christensen, et al., Eur.J. Pharmacol., 41, 153 (1977), and reports of its clinical effectivenessin depression may be found in Dufour, et al., Int. Clin.Psychopharmacol., 2, 225 (1987), and Timmerman, et al., ibid., 239.

Fluvoxamine, 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanoneO-(2-aminoethyl)oxime, is taught by U.S. Pat. No. 4,085,225. Scientificarticles about the drug have been published by Claassen, et al., Brit.J. Pharmacol., 60, 505 (1977); and De Wilde, et al., J. AffectiveDisord., 4, 249 (1982); and Benfield, et al., Drugs, 32, 313 (1986).

Paroxetine,trans-(−)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine,may be found in U.S. Pat. Nos. 3,912,743 and 4,007,196. Reports of thedrug's activity are in Lassen, Eur. J. Pharmacol., 47, 351 (1978);Hassan, et al.,Brit. J. Clin. Pharmacol., 19, 705 (1985); Laursen, etal., Acta Psychiat. Scand., 71, 249 (1985); and Battegay, et al.,Neuropsychobiology, 13, 31 (1985).

All of the U.S. patents which have been mentioned above in connectionwith compounds used in the present invention are incorporated herein byreference.

In general, combinations and methods of treatment using fluoxetine orduloxetine as the SRI are preferred.

It will be understood by the skilled reader that all of the compoundsused in the present invention are capable of forming salts, and that thesalt forms of pharmaceuticals are commonly used, often because they aremore readily crystallized and purified than are the free bases. In allcases, the use of the pharmaceuticals described above as salts iscontemplated in the description herein, and often is preferred, and thepharmaceutically acceptable salts of all of the compounds are includedin the names of them.

The dosages of the drugs used in the present combination must, in thefinal analysis, be set by the physician in charge of the case, usingknowledge of the drugs, the properties of the drugs in combination asdetermined in clinical trials, and the characteristics of the patient,including diseases other than that for which the physician is treatingthe patient. General outlines of the dosages, and some preferreddosages, are provided. Dosage guidelines for some of the drugs willfirst be given separately; in order to create a guideline for anydesired combination, one would choose the guidelines for each of thecomponent drugs.

Fluoxetine: from about 1 to about 80 mg, once/day; preferred, from about10 to about 40 mg once/day; preferred for bulimia andobsessive-compulsive disease, from about 20 to about 80 mg once/day;

Duloxetine: from about 1 to about 30 mg once/day; preferred, from about5 to about 20 mg once/day;

Venlafaxine: from about 10 to about 150 mg once-thrice/day; preferred,from about 25 to about 125 mg thrice/day;

Milnacipran: from about 10 to about 100 mg once-twice/day; preferred,from about 25 to about 50 mg twice/day;

Citalopram: from about 5 to about 50 mg once/day; preferred, from about10 to about 30 mg once/day;

Fluvoxamine: from about 20 to about 500 mg once/day; preferred, fromabout 50 to about 300 mg once/day;

Paroxetine: from about 5 to about 100 mg once/day; preferred, from about50 to about 300 mg once/day.

In more general terms, one would create a combination of the presentinvention by choosing a dosage of SRI according to the spirit of theabove guideline, and choosing a dosage of the compound of Formula I orformula Ia in the ranges taught above.

The adjunctive therapy of the present invention is carried out byadministering a SRI together with a compound of Formula I or formula Iain any manner which provides effective levels of the two compounds inthe body at the same time. All of the compounds concerned are orallyavailable and are normally administered orally, and so oraladministration of the adjunctive combination is preferred. They may beadministered together, in a single dosage form, or may be administeredseparately.

However, oral administration is not the only route or even the onlypreferred route. For example, transdermal administration may be verydesirable for patients who are forgetful or petulant about taking oralmedicine. One of the drugs may be administered by one route, such asoral, and the other may be administered by the trans-dermal,percutaneous, intravenous, intramuscular, intranasal or intrarectalroute, in particular circumstances. The route of administration may bevaried in any way, limited by the physical properties of the drugs andthe convenience of the patient and the caregiver.

It is particularly preferred, however, for the adjunctive combination tobe administered as a single pharmaceutical composition, and sopharmaceutical compositions incorporating both a SRI and a compound ofFormula I or formula Ia are important embodiments of the presentinvention. Such compositions may take any physical form which ispharmaceutically acceptable, but orally usable pharmaceuticalcompositions are particularly preferred. Such adjunctive pharmaceuticalcompositions contain an effective amount of each of the compounds, whicheffective amount is related to the daily dose of the compounds to beadministered. Each adjunctive dosage unit may contain the daily doses ofboth compounds, or may contain a fraction of the daily doses, such asone-third of the doses. Alternatively, each dosage unit may contain theentire dose of one of the compounds, and a fraction of the dose of theother compound. In such case, the patient would daily take one of thecombination dosage units, and one or more units containing only theother compound. The amounts of each drug to be contained in each dosageunit depends on the identity of the drugs chosen for the therapy, andother factors such as the indication for which the adjunctive therapy isbeing given.

As stated above, the benefit of the adjunctive therapy is its ability toaugment the increase in availability of serotonin, norepinephrine anddopamine caused by the SRI compounds, resulting in improved activity intreating the various conditions described below in detail. The increasein availability of serotonin is particularly important and is apreferred aspect of the invention. Further, the invention provides amore rapid onset of action than is usually provided by treatment withthe SRI alone.

Preferred pathological conditions to be treated by the present method ofadjunctive therapy include depression, bulimia, obsessive-compulsivedisease and obesity. Another preferred condition more specific tocombinations including preferably duloxetine but also venlafaxine andmilnacipran is urinary incontinence.

Depression in its many variations has recently become much more visibleto the general public than it has previously been. It is now recognizedas an extremely damaging disorder, and one that afflicts a surprisinglylarge fraction of the population. Suicide is the most extreme symptom ofdepression, but millions of people, not quite so drastically afflicted,live in misery and partial or complete uselessness, and afflict theirfamilies as well by their affliction. The introduction of fluoxetine wasa breakthrough in the treatment of depression, and depressives are nowmuch more likely to be diagnosed and treated than they were only adecade ago. Duloxetine is in clinical trials for the treatment ofdepression.

Depression is often associated with other diseases and conditions, orcaused by such other conditions. For example, it is associated withParkinson's disease; with HIV; with Alzheimer's disease; and with abuseof anabolic steroids. Depression may also be associated with abuse ofany substance, or may be associated with behavioral problems resultingfrom or occurring in combination with head injuries, mental retardationor stroke. Depression in all its variations is a preferred target oftreatment with the present adjunctive therapy method and compositions.

Obsessive-compulsive disease appears in a great variety of degrees andsymptoms, generally linked by the patient's uncontrollable urge toperform needless, ritualistic acts. Acts of acquiring, ordering,cleansing and the like, beyond any rational need or rationale, are theoutward characteristic of the disease. A badly afflicted patient may beunable to do anything but carry out the rituals required by the disease.Fluoxetine is approved in the United States and other countries for thetreatment of obsessive-compulsive disease and has been found to beeffective.

Obesity is a frequent condition in the American population. It has beenfound that fluoxetine will enable an obese patient to lose weight, withthe resulting benefit to the patient's circulation and heart condition,as well as general well being and energy.

Urinary incontinence is classified generally as stress or urgeincontinence, depending on whether its root cause is the inability ofthe sphincter muscles to keep control, or the overactivity of thebladder muscles. Duloxetine controls both types of incontinence, or bothtypes at once, and so is important to the many people who suffer fromthis embarrassing and disabling disorder.

The present combination is useful for treating many other diseases,disorders and conditions as well, as set out below. In many cases, thediseases to be mentioned here are classified in the InternationalClassification of Diseases, 9th Edition (ICD), or in the Diagnostic andStatistical Manual of Mental Disorders, 3rd Version Revised, publishedby the American Psychiatric Association (DSM). In such cases, the ICD orDSM code numbers are supplied below for the convenience of the reader.

depression, ICD 296.2 & 296.3, DSM 296, 294.80, 293.81, 293.82, 293.83,310.10, 318.00, 317.00

migraine pain, particularly neuropathic pain bulimia, ICD 307.51, DSM307.51

premenstrual syndrome or late luteal phase syndrome, DSM 307.90

alcoholism, ICD 305.0, DSM 305.00 & 303.90

tobacco abuse, ICD 305.1, DSM 305.10 & 292.00

panic disorder, ICD 300.01, DSM 300.01 & 300.21

anxiety, ICD 300.02, DSM 300.00

post-traumatic syndrome, DSM 309.89

memory loss, DSM 294.00

dementia of aging, ICD 290

social phobia, ICD 300.23, DSM 300.23

attention deficit hyperactivity disorder, ICD 314.0

disruptive behavior disorders, ICD 312

impulse control disorders, ICD 312, DSM 312.39 & 312.34

borderline personality disorder, ICD 301.83, DSM 301.83

chronic fatigue syndrome

premature ejaculation, DSM 302.75

erectile difficulty, DSM 302.72

anorexia nervosa, ICD 307.1, DSM 307.10

disorders of sleep, ICD 307.4

autism

mutism

trichotillomania

Further, the compounds of Formula I or formula Ia are particularlyuseful for alleviating the symptoms of smoking cessation or nicotinewithdrawal when administered in combination with a serotonin reuptakeinhibitor. The SRI's to be used in this treatment method, and theadministration methods and formulations, are as described above. The useof the present compounds with SRI's in patients striving to stop use oftobacco or nicotine provides surprisingly complete alleviation of theusual painful and damaging symptoms of such patients, includingnervousness, irritability, craving, excessive appetite, anxiety,depression in many forms, inability to concentrate, and the like.

Therapeutic Applications

The compounds of Formula I or formula Ia are useful for other importanttherapeutic purposes, as well as in combination with SRIs and innicotine withdrawal or smoking cessation cases. In particular, thecompounds are useful for antagonism at the serotonin 1A receptor andaccordingly are used for the treatment or prevention of conditionscaused by or affected by excessive activity of that receptor.

More particularly, the compounds of Formula I or formula Ia are usefulin the treatment of anxiety, depression, hypertension, cognitivedisorders, psychosis, sleep disorders, gastric motility disorders,sexual dysfunction, brain trauma, memory loss, appetite disorders andobesity, substance abuse, obsessive-compulsive disease, panic disorderand migraine.

Anxiety and its frequent concomitant, panic disorder, may beparticularly mentioned in connection with the present compounds. Thesubject is carefully explained by the Diagnostic and Statistical Manualof Mental Disorders, published by the American Psychiatric Association,which classifies anxiety under its category 300.02. A furtherparticularly noted disorder is depression and the group ofdepression-related disorders, which are discussed above in thediscussion of adjunctive therapy with SRIs.

Pharmaceutical Compositions

It is customary to formulate pharmaceuticals for administration, toprovide control of the dosage and stability of the product in shipmentand storage, and the usual methods of formulation are entirelyapplicable to the compounds of Formula I and formula Ia. Suchcompositions, comprising at least one pharmaceutically acceptablecarrier, are valuable and novel because of the presence of the compoundsof Formula I or formula Ia therein. Although pharmaceutical chemists arewell aware of many effective ways to formulate pharmaceuticals, whichtechnology is applicable to the present compounds, some discussion ofthe subject will be given here for the convenience of the reader.

The usual methods of formulation used in pharmaceutical science and theusual types of compositions may be used, including tablets, chewabletablets, capsules, solutions, parenteral solutions, intranasal sprays orpowders, troches, suppositories, transdermal patches and suspensions. Ingeneral, compositions contain from about 0.5% to about 50% of thecompound in total, depending on the desired dose and the type ofcomposition to be used. The amount of the compound of Formula I orformula Ia, however, is best defined as the effective amount, that is,the amount of the compound which provides the desired dose to thepatient in need of such treatment. The activity of the compounds do notdepend on the nature of the composition, so the compositions are chosenand formulated solely for convenience and economy. Any compound may beformulated in any desired form of composition. Some discussion ofdifferent compositions will be provided, followed by some typicalformulations.

Capsules are prepared by mixing the compound with a suitable diluent andfilling the proper amount of the mixture in capsules. The usual diluentsinclude inert powdered substances such as starch of many differentkinds, powdered cellulose, especially crystalline and microcrystallinecellulose, sugars such as fructose, mannitol and sucrose, grain floursand similar edible powders.

Tablets are prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant is necessary in a tablet formulation to prevent the tabletand punches from sticking in the die. The lubricant is chosen from suchslippery solids as talc, magnesium and calcium stearate, stearic acidand hydrogenated vegetable oils.

Tablet disintegrators are substances which swell when wetted to break upthe tablet and release the compound. They include starches, clays,celluloses, algins and gums. More particularly, corn and potatostarches, methylcellulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used, as well assodium lauryl sulfate.

Enteric formulations are often used to protect an active ingredient fromthe strongly acidic contents of the stomach. Such formulations arecreated by coating a solid dosage form with a film of a polymer which isinsoluble in acidic environments, and soluble in basic environments.Exemplary films are cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate.

Tablets are often coated with sugar as a flavor and sealant, or withfilm-forming protecting agents to modify the dissolution properties ofthe tablet. The compounds may also be formulated as chewable tablets, byusing large amounts of pleasant-tasting substances such as mannitol inthe formulation, as is now well-established practice. Instantlydissolving tablet-like formulations are also now frequently used toassure that the patient consumes the dosage form, and to avoid thedifficulty in swallowing solid objects that bothers some patients.

When it is desired to administer the combination as a suppository, theusual bases may be used. Cocoa butter is a traditional suppository base,which may be modified by addition of waxes to raise its melting pointslightly. Water-miscible suppository bases comprising, particularly,polyethylene glycols of various molecular weights are in wide use, also.

Transdermal patches have become popular recently. Typically theycomprise a resinous composition in which the drugs will dissolve, orpartially dissolve, which is held in contact with the skin by a filmwhich protects the composition. Many patents have appeared in the fieldrecently. Other, more complicated patch compositions are also in use,particularly those having a membrane pierced with innumerable poresthrough which the drugs are pumped by osmotic action.

The following typical formulae are provided for the interest andinformation of the pharmaceutical scientist.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Example 1  20 mg Starch, dried 200 mg Magnesiumstearate  10 mg Total 230 mg

Formulation 2

A tablet is prepared using the ingredients below:

Quantity (mg/capsule) Example 2  10 mg Cellulose, microcrystalline 400mg Silicon dioxide, fumed  10 mg Stearic acid  5 mg Total 425 mg

The components are blended and compressed to form tablets each weighing425 mg.

Formulation 3

Tablets, each containing 10 mg of active ingredient, are made asfollows:

Example 3 10 mg Starch 45 mg Microcrystalline cellulose 35 mgPolyvinylpyrrolidone  4 mg (as 10% solution in water) Sodiumcarboxymethyl starch 4.5 mg  Magnesium stearate 0.5 mg  Talc  1 mg Total100 mg 

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinyl-pyrrolidone is mixed with the resultant powder, and themixture then is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.Sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 100 mg.

Formulation 4

Capsules, each containing 30 mg of active ingredient, are made asfollows:

Example 4 30 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesiumstearate  2 mg Total 150 mg 

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

Formulation 5

Suppositories, each containing 5 mg of active ingredient, are made asfollows:

Example 5    5 mg Saturated fatty acid glycerides 2,000 mg Total 2,005mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 6

Suspensions, each containing 10 mg of active ingredient per 5 ml dose,are made as follows:

Example 6 10 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mlBenzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified water tototal 5 ml

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 7

An intravenous formulation may be prepared as follows:

Example 7 10 mg Isotonic saline 1,000 ml

Formulation 8

Hard gelatin capsules are prepared in a manner analogous to formulation1 using the following ingredients:

Quantity (mg/capsule) (+)-1-(2-Methoxyphenyl)-4-[3-  20 mg(cyclohexanecarbonyl)-3- (phenyl)butyl]piperazine HCl Starch, dried 200mg Magnesium stearate  10 mg Total 230 mg

Formulation 9

A tablet is prepared using the ingredients below:

Quantity (mg/capsule) (+)-1-(2-Methoxyphenyl)-4-[3-  10 mg(cyclohexanecarbonyl)-3- (phenyl)butyl]piperazine HCl Cellulose,microcrystalline 400 mg Silicon dioxide, fumed  10 mg Stearic acid  5 mgTotal 425 mg

The components are blended and compressed to form tablets each weighing425 mg in a manner analogous to formulation 2.

Formulation 10

Tablets, each containing 10 mg of active ingredient, are made asfollows:

(+)-1-(2-Methoxyphenyl)-4-[3- 10 mg (cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine HCl Starch 45 mg Microcrystalline cellulose 35mg Polyvinylpyrrolidone (as 10% solution in water)  4 mg Sodiumcarboxymethyl starch 4.5 mg  Magnesium stearate 0.5 mg  Talc  1 mg Total100 mg 

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinyl- pyrrolidone is mixed with the resultant powder, and themixture then is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.Sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 100 mg.

Formulation 11

Capsules, each containing 30 mg of active ingredient, are made asfollows in a manner analogous to formulation 4:

(+)-1-(2-Methoxyphenyl)-4-[3- 30 mg (cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine HCl Starch 59 mg Microcrystalline cellulose 59mg Magnesium stearate  2 mg Total 150 mg 

We claim:
 1. A compound of the formula

wherein Ar′ is a phenyl or pyridyl substituted with one to threesubstituents selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-₆)alkylthio, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylhalo, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenylor halo; R¹ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio;R² is phenyl, naphthyl or (C₃-C₁₂)cycloalkyl substituted with one or twosubstituents selected from the group consisting of hydrogen(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylhalo, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenylor halo; R³ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylhalo, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenylor halo; X is —(C═O)—; or a pharmaceutically acceptable salt, racemate,or optical isomer thereof.
 2. A compound of claim 1 wherein Ar′ isphenyl or pyridyl.
 3. A compound of claim 2 wherein Ar′ is phenylsubstituted with (C₁-C₆)alkoxy.
 4. A compound of claim 3 wherein R² isphenyl or (C₃-C₁₂)cycloalkyl.
 5. A compound of claim 4 wherein R¹ ishydrogen.